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Brain Res. 2007 Apr 6;1140:105-19. Epub 2005 Dec 20.

Functional compensation by other voltage-gated Ca2+ channels in mouse basal forebrain neurons with Ca(V)2.1 mutations.

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Department of Medical Pharmacology and Toxicology, College of Medicine, Reynolds Medical Science Building, Texas A&M University System Health Science Center, 1114-TAMU, College Station, TX 77843-1114, USA.


Tottering (tg/tg) and leaner (tg(la)/tg(la)) mutant mice exhibit distinct mutations in the gene encoding the voltage-activated Ca(2+) channel alpha(1A) subunit (CACNA1A), the pore-forming subunit of the Ca(V)2.1 (P/Q type) Ca(2+) channels. These mice exhibit absence seizures and deficiencies in motor control and other functions. Previous work in cerebellar Purkinje neurons has shown that these mutations cause dramatic reductions in calcium channel function. Because Purkinje cell somata primarily express the Ca(V)2.1 channels, the general decrease in Ca(V)2.1 channel function is observed as a profound decrease in whole-cell current. In contrast to Purkinje cells, basal forebrain (BF) neurons express all of the Ca(2+) channel alpha(1) subunits, with Ca(V)2.1 contributing approximately 30% to the whole-cell current in wild-type (+/+) mice. Here, we show that whole-cell Ba(2+) current densities in BF neurons are not reduced in the mutant genotypes despite a reduction in the Ca(V)2.1 contribution. By blocking the different Ca(2+) channel subtypes with specific pharmacological agents, we found a significant increase in the proportion of Ca(V)1 Ca(2+) current in mutant phenotypes. There was no change in tissue mRNA expression of calcium channel subtypes Ca(V)2.1, Ca(V)2.2, Ca(V)1.2, Ca(V)1.3, and Ca(V)2.3 in the tottering and leaner mutant mice. These results suggest that Ca(V)1 channels may functionally upregulate to compensate for reduced Ca(V)2.1 function in the mutants without an increase in Ca(v)1 message. Single-cell reverse transcription polymerase chain reaction (RT-PCR) experiments in a subset of sampled neurons revealed that approximately 90% of the cells could be considered cholinergic based on choline acetyltransferase (ChAT) mRNA expression.

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